title: Chronic heart failure is associated with transforming growth factor beta-dependent yield and functional decline in atrial explant-derived c-Kit+ cells.
abstract: BACKGROUND
  Cardiac c-Kit+ cells isolated from cardiac explant-derived cells modestly improve cardiac functions after myocardial infarction; however, their full potential has not yet been realized. For instance, the majority of potential candidates for cell therapy suffer from chronic heart failure (CHF), and it is unclear how this disease affects the explant-derived progenitor cells. Therefore, the objective of this study was to determine the effect of CHF on the number and phenotype of cardiac explant c-Kit+ progenitors and elucidate mechanisms of their regulation.
  
  
  RESULTS
  Myocardial infarction was created by left anterior descending coronary artery occlusion. Sham-operated animals were used as a control group. CHF-developed infarcted animals were selected on the basis of left ventricle end-diastolic pressure ≥ 20 mm Hg and scar size ≥ 30%. Here, we found that CHF atrial explants produced less c-Kit+ cells than sham explants. CHF-derived c-Kit+ cells exhibited upregulated transforming growth factor-β (TGF-β) signaling, increased level of epithelial to mesenchymal transition markers, and diminished expression of pluripotency markers compared with shams. We show that intervention with TGF-β signaling by inhibiting TGF-β receptor type I or Smad 2/3 using small-molecule inhibitors improved c-Kit+ cell yield, attenuated epithelial to mesenchymal transition markers, stimulated the pluripotency marker Nanog, and improved efficiency of c-Kit+ cell differentiation toward cardiomyocyte-like cells in vitro.
  
  
  CONCLUSIONS
  Taken together, our findings suggest that TGF-β inhibition positively modulates c-Kit+ cell phenotype and function in vitro, and this strategy may be considered in optimizing cardiac progenitor function and cell expansion protocols for clinical application.
authors.affiliation: Center for Cardiovascular Research at Banner Sun Health Research Institute, Sun City, AZ.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Zakharova
authors.forename: Hikmet
authors.initials: H
authors.lastname: Nural-Guvener
authors.forename: James
authors.initials: J
authors.lastname: Nimlos
authors.forename: Snjezana
authors.initials: S
authors.lastname: Popovic
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Gaballa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D006325:Heart Atria / Q000166:cytology*; D006333:Heart Failure / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta
keywords: cell transplantation; chronic heart failure; heart; signaling pathways; stem cell